Direct fluid coating of drug eluting balloon

ABSTRACT

A system and method for coating an expandable member of a medical device comprises providing a dispenser in fluid communication with a fluid source with the dispenser having at least one outlet to dispense fluid of the fluid source therefrom. The outlet(s) of the dispenser is positioned proximate a surface of an expandable member, with relative movement between the outlet(s) and the surface of the expandable member established along a coating path, and fluid is dispensed from the dispenser to form a substantially continuous bead of fluid between the at least one outlet and the surface of the expandable member along the coating path, and simultaneously drying the fluid while dispensing the fluid from the dispenser to control flow of fluid on the surface of the expandable member. The fluid source can include a variety of therapeutic agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.13/108,283, filed May 16, 2011, which claims priority to U.S.Provisional Application No. 61/345,575 entitled “Direct fluid coating ofdrug eluting balloon,” filed May 17, 2010 which is incorporated hereinby reference in its entirety.

BACKGROUND OF THE DISCLOSED SUBJECT MATTER

1. Field of the Disclosed Subject Matter

The presently disclosed subject matter is related to the delivery oftherapeutic agents from an interventional medical device. Moreparticularly, the presently disclosed subject matter relates to aninterventional device for delivery of therapeutic agents from anexpandable member, such as a balloon. The disclosed subject matter alsorelates to a method and apparatus for applying one or more therapeuticagents onto the expandable member as well as the assembly of the medicaldevice.

2. Description of related Subject Matter

Atherosclerosis is a syndrome affecting arterial blood vessels. It ischaracterized by a chronic inflammatory response in the walls ofarteries, which is in large part due to the accumulation of lipid,macrophages, foam cells and the formation of plaque in the arterialwall. Atherosclerosis is commonly referred to as hardening of thearteries, although the pathophysiology of the disease manifests itselfwith several different types lesions ranging from fibrotic to lipidladen to calcific. Angioplasty is a vascular interventional techniqueinvolving mechanically widening an obstructed blood vessel, typicallycaused by atherosclerosis.

During angioplasty, a catheter having a folded balloon is inserted intothe vasculature of the patient and is passed to the narrowed location ofthe blood vessel at which point the balloon is inflated to the desiredsize by fluid pressure. Percutaneous coronary intervention (PCI),commonly known as coronary angioplasty, is a therapeutic procedure totreat the stenotic regions in the coronary arteries of the heart, oftenfound in coronary heart disease. In contrast, peripheral angioplasty,commonly known as percutaneous transluminal angioplasty (PTA), generallyrefers to the use of mechanical widening of blood vessels other than thecoronary arteries. PTA is most commonly used to treat narrowing of theleg arteries, especially, the iliac, external iliac, superficial femoraland popliteal arteries. PTA can also treat narrowing of carotid andrenal arteries, veins, and other blood vessels.

Although the blood vessel is often successfully widened by angioplasty,sometimes the treated region of the blood vessel undergoes vasospasm, orabrupt closure after balloon inflation or dilatation, causing the bloodvessel to collapse after the balloon is deflated or shortly thereafter.One solution to such collapse is stenting the blood vessel to preventcollapse. Dissection, or perforation, of the blood vessel is anothercomplication of angioplasty that can be improved by stenting. A stent isa device, typically a metal tube or scaffold that is inserted into theblood vessel after, or concurrently with angioplasty, to hold the bloodvessel open.

While the advent of stents eliminated many of the complications ofabrupt vessel closure after angioplasty procedures, within about sixmonths of stenting a re-narrowing of the blood vessel can form, acondition known as restenosis. Restenosis was discovered to be aresponse to the injury of the angioplasty procedure and is characterizedby a growth of smooth muscle cells and extracellular matrix analogous toa scar forming over an injury. To address this condition, drug elutingstents were developed to reduce the reoccurrence of blood vesselnarrowing after stent implantation. A drug eluting stent is a stent thathas been coated with a drug, often in a polymeric carrier, that is knownto interfere with the process of re-narrowing of the blood vessel(restenosis). Examples of various known drug eluting stents aredisclosed in U.S. Pat. Nos. 5,649,977; 5,464,650; 5,591,227, 7,378,105;7,445,792; 7,335,227, each of which are hereby incorporated by referencein their entirety. However, a drawback of drug eluting stents is acondition known as late stent thrombosis. This is an event where a bloodclot forms inside the stent, which can occlude blood flow.

Drug coated balloons are believed to be a viable alternative to drugeluting stents in the treatment of atherosclerotic lesions. In a studywhich evaluated restenosis, and the rate of major adverse cardiac eventssuch as heart attack, bypass, repeat stenosis, or death in patientstreated with drug coated balloons and drug eluting stents, the patientstreated with drug coated balloons experienced only 3.7 percentrestenosis and 4.8% MACE (material adverse coronary events) as comparedto patients treated with drug eluting stents, in which restenosis was20.8 percent and 22.0 percent MACE rate. (See, PEPCAD II study,Rotenburg, Germany).

However, drug coated balloons present certain unique challenges. Forexample, the drug carried by the balloon needs to remain on the balloonduring delivery to the lesion site, and released from the balloonsurface to the blood vessel wall when the balloon is expanded inside theblood vessel. For coronary procedures, the balloon is typically inflatedfor less than one minute, typically about thirty seconds. The ballooninflation time may be longer for a peripheral procedure, howevertypically even for peripheral procedures the balloon is expanded forless than 5 minutes. Due to the short duration of contact between thedrug coated balloon surface and the blood vessel wall, the ballooncoating must exhibit efficient therapeutic agent transfer and/orefficient drug release during inflation. Thus, there are challengesspecific to drug delivery via a drug coated or drug eluting balloon thatare not present with a drug eluting stent.

Furthermore, conventional techniques for applying a coating, such as atherapeutic agent, may not be desirable for coating balloons, or otherexpandable members of medical devices. Such convention techniquesinclude spraying (air-atomization, ultrasonic, electrostatic, etc.),dip-coating, spin-coating, vapor deposition, roll coating, micro-dropletcoating, etc. Balloons present a cylindrical surface to be coated whereit is desired to uniformly coat only the working length of the balloonand no other portion of the balloon or catheter. Many of theseconventional techniques do not provide sufficient coating uniformity oredge control. Moreover, many of these techniques are not efficient intheir utilization of the therapeutic agent that can be costly. Forexample, with the spray coating techniques commonly used to coat drugeluting stents, only a fraction of the therapeutic agent discharged isretained on the surface of the medical device. This inefficiency isexacerbated with medical devices having larger surface areas, such asperipheral balloons, wherein the amount of therapeutic agent retained onthe device can be as low as 2% of the amount of therapeutic agentdischarged.

Thus there remains a need, and an aim of the disclosed subject matter isdirected towards, the application of one or more therapeutic agents tothe surface of an expandable member of a medical device.

SUMMARY OF THE DISCLOSED SUBJECT MATTER

The purpose and advantages of the disclosed subject matter will be setforth in and are apparent from the description that follows, as well aswill be learned by practice of the disclosed subject matter. Additionaladvantages of the disclosed subject matter will be realized and attainedby the methods and systems particularly pointed out in the writtendescription and claims hereof, as well as from the appended drawings.

To achieve these and other advantages and in accordance with the purposeof the disclosed subject matter, as embodied and broadly described, thedisclosed subject matter includes a system and method of coating anexpandable member of a medical device. The method comprises providing adispenser in fluid communication with a fluid source containing at leastone therapeutic agent, with the dispenser having at least one outlet todispense fluid of the fluid source, and positioning the at least oneoutlet of the dispenser in proximity to a surface of an expandablemember. Relative movement is established between the at least one outletand the surface of the expandable member along a coating path, and fluidis dispensed from the dispenser to form a substantially continuous beadof fluid between the outlet(s) and the surface of the expandable memberalong the coating path, and simultaneously drying the fluid whiledispensing the fluid from the dispenser to control flow of fluid on thesurface of the expandable member.

The relative movement includes rotation, translation, or a combinationthereof about at least one axis, of at least one of the expandablemembers and the at least one outlet. Additionally, the relative movementcan further include rotation, axial translation, or a combinationthereof, of the other of the expandable member and the at least oneoutlet. For example, the relative movement can define a helical path ofthe outlet with respect to the expandable member, and/or the expandablemember is moved along a first axis, and the outlet can be moved along asecond axis transverse to the first axis.

The dispensing of fluid to the surface of the expandable member can berepeated along a plurality of coating paths. Additionally, oralternatively, a first fluid can be dispensed during a first coatingpath, and a second fluid can be dispensed during a second coating path.Additionally, the method can include drying the fluid on the surfacebetween successive coating paths. The drying of the fluid on the surfacecan occur at specific periods before and after dispensing orsimultaneously with the dispensing of the fluid along the coating path.The dispensing of fluid can be controlled to apply a substantiallyuniform or non-uniform coating of fluid to a predetermined area of theexpandable member. The method also includes at least partially expandingthe expandable member prior to dispensing fluid to the surface of theexpandable member.

The dispenser is selected from the group including pipet tubing,flexible tubing, coaxial tubing, hypotubes, dies, ball-bearing dispensetubing, syringe, needles, and other non-contacting applicators capableof forming a continuous bead. Additionally, the dispenser can include aplurality of outlets arranged along a common axis, angularly offset formeach other, or combinations thereof. Each dispenser outlet can be incommunication with a different fluid source, and can be heated duringthe dispensing operation.

The disclosed subject matter also includes a system for coating anexpandable member of a medical device. The system includes a supportstructure to support an expandable member of a medical device, and adispenser in fluid communication with a fluid source and having at leastone outlet for dispensing fluid of the fluid source therefrom, whereinthe dispenser can be positioned with the at least one outlet proximate asurface of an expandable member supported by the support structure. Adryer is provided proximate the dispenser to simultaneously dry thefluid while dispensing the fluid from the dispenser to control flow offluid on the surface of the expandable member. A drive assembly isemployed to establish relative movement between the at least one outletand the surface of the expandable member to dispense fluid from thedispenser as a substantially continuous bead between the at least oneoutlet and the surface of the expandable member along a coating path.

The dispenser is capable of varying the rate in which fluid is dispensedfrom the at least one outlet. Additionally, the drive assembly iscapable of varying the speed of relative movement between the at leastone outlet and the surface of the expandable member, as well asestablishing a plurality of coating paths for delivery of fluid from thedispenser to the surface of the expandable member. A dryer can beprovided to apply heat, forced gas, cold temperature, vacuum, infra-redenergy, microwave energy, or a combination thereof to the surface of theexpandable member.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and are intended toprovide further explanation of the disclosed subject matter claimed.

The accompanying drawings, which are incorporated in and constitute partof this specification, are included to illustrate and provide a furtherunderstanding of the method and system of the disclosed subject matter.Together with the description, the drawings serve to explain theprinciples of the disclosed subject matter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic side view representative balloon catheter inaccordance with the disclosed subject matter.

FIG. 1A is a cross-sectional view taken along lines A-A in FIG. 1.

FIG. 1B is a cross-sectional view taken along lines B-B in FIG. 1.

FIG. 2 is a schematic representative view of direct fluid coating inaccordance with the disclosed subject matter.

FIG. 3 is a schematic representation of a dispenser and drying apparatusin accordance with the disclosed subject matter.

FIG. 4 is a schematic cross-sectional view of the dispenser and dryingapparatus of FIG. 3.

FIG. 5 is a schematic cross-sectional view of a support assembly forsupporting the shaft of the catheter during a coating process.

DETAILED DESCRIPTION

Reference will now be made in detail to embodiments of the disclosedsubject matter, an example of which is illustrated in the accompanyingdrawing. The method and corresponding steps of the disclosed subjectmatter will be described in conjunction with the detailed description ofthe system.

The methods and systems presented herein can be used for applying one ormore coatings to a medical device. The disclosed subject matter isparticularly suited for directly applying therapeutic agents, and otherfluid compounds, to select portions of an expandable member. While thedisclosed subject matter references application of a fluid to anexpandable member, it is to be understood that the methods and systemsdisclosed herein can also be employed to apply therapeutic, polymeric,or matrix coatings to various surfaces of medical devices, as sodesired.

The disclosed subject matter provides a method, and correspondingsystem, to coat an expandable member, or select portions thereof, by adirect application process. The direct application process applies acoating without atomization, or the formation of droplets, of thecoating fluid. Additionally, the disclosed subject matter provides asystem and method for improved efficiency of the dispensing of a coatingsolution, which can be controlled based on the volume of coatingsolution dispensed, rather than via a weight based control. Indeed, thedisclosed subject matter provides a system and method for dispensing ofa coating solution which can achieve 95.0% or greater transferefficiency, i.e., 95.0% of the coating solution dispensed is applied tothe expandable member.

In accordance with the disclosed subject matter, a method of coating anexpandable member of a medical device comprises providing a dispenser influid communication with a fluid source with the dispenser having atleast one outlet to dispense fluid of the fluid source therefrom. The atleast one outlet of the dispenser is positioned proximate a surface ofan expandable member, with relative movement between the at least oneoutlet and the surface of the expandable member established along acoating path, and fluid is dispensed from the dispenser to form asubstantially continuous bead of fluid between the outlet and thesurface of the expandable member along the coating path.

For purpose of explanation and illustration, and not limitation, anexemplary embodiment of a medical device having an expandable member isshown schematically in FIGS. 1 and 1A. Particularly, and as illustrated,the medical device embodied herein is a balloon catheter 10, whichincludes an elongated catheter shaft 12 having a proximal end and havinga distal end and an expandable member 30 located proximate the distalend of the catheter shaft. The expandable member, or balloon as depictedherein, has an outer surface and an inner surface disposed at the distalend portion of the catheter shaft. In accordance with the disclosedsubject matter, a coating is applied to at least a portion of the outersurface of the balloon.

The elongated catheter shaft 12 comprises an outer tubular member 14 andan inner tubular member 16. The outer tubular member 14 defines aninflation lumen 20 disposed between the proximal end portion and thedistal end portion of the catheter shaft 12. Specifically, asillustrated in FIG. 1A, the coaxial relationship of this representativeembodiment defines an annular inflation lumen 20 between the innertubular member 16 and the outer tubular member 14. The expandable member30 is in fluid communication with the inflation lumen 20. The inflationlumen can supply an inflation medium under positive pressure and canwithdraw the inflation medium, i.e. provide negative pressure, from theexpandable member. The expandable member 30 can thus be inflated anddeflated. The elongated catheter is sized and configured for deliverythrough a tortuous anatomy, and can further include a guidewire lumen 22that permits it to be delivered over a guidewire 18. As illustrated inFIG. 1A, the inner tubular member 16 defines the guidewire lumen 22 forthe guidewire 18. Although FIGS. 1 and 1 b illustrate the guidewirelumen as having an over-the-wire (OTW) construction, the guidewire lumencan be configured as a rapid-exchange (RX) construction, as is wellknown in the art.

A wide variety of balloon catheters and balloon constructs are known andsuitable for use in accordance with the disclosed subject matter. Forexample, the expandable member can be made from polymeric material suchas compliant, non-compliant or semi-compliant polymeric material orpolymeric blends. Examples of such suitable materials include, but arenot limited to, nylon 12, nylon 11, nylon 9, nylon 6, nylon 6/12, nylon6/11, nylon 6/9, and nylon 6/6, polyurethane, silicone-polyurethane,polyesters, polyester copolymers, and polyethylene. Examples of otherballoon and catheter embodiments which can be employed in accordancewith the disclosed subject matter include U.S. Pat. Nos. 4,748,982;5,496,346; 5,626,600; 5,300,085, 6,406,457 and U.S. application Ser.Nos. 12/371,426; 11/539,944; 12/371,422, each of which is herebyincorporated by reference in their entirety.

In one embodiment, the coating is applied to the expandable member ofthe fully assembled medical device. As described above with reference toFIGS. 1A-B, medical devices such as the catheter 10 include a pluralityof components which are typically manufactured as separate discretecomponents and thereafter assembled together. Applying a coating to theexpandable member at an upstream stage of an assembly line requiresextensive measures to minimize or prevent the coating from being exposedto various equipment and processes during the downstream portion of theassembly line. Such exposure can render the coating prone to damageand/or contamination during final assembly of the catheter, and canresult in scrapping of the entire catheter. In order to avoid suchexposure and damage to the coating in conventional catheter assemblylines additional equipment including monitoring and safety controlswould be required. Accordingly, applying the coating to the expandablemember of a fully assembled catheter avoids the unnecessary complexity,and excessive costs associated with such a modified assembly line.

In accordance with the disclosed subject matter, any of a variety offluid compositions can be applied to the expandable member. For example,the fluid can include a therapeutic agent for treatment of a diseasestate. Examples of suitable therapeutic agents includeanti-proliferative, anti-inflammatory, antineoplastic, antiplatelet,anti-coagulant, anti-fibrin, antithrombotic, antimitotic, antibiotic,antiallergic and antioxidant compounds. Such therapeutic agents can be,again without limitation, a synthetic inorganic or organic compound, aprotein, a peptide, a polysaccharides and other sugars, a lipid, DNA andRNA nucleic acid sequences, an antisense oligonucleotide, an antibodies,a receptor ligands, an enzyme, an adhesion peptide, a blood clot agentincluding streptokinase and tissue plasminogen activator, an antigen, ahormone, a growth factor, a ribozyme, and a retroviral vector. However,the therapeutic agents can include, cytostatic drug. The term“cytostatic” as used herein means a drug that mitigates cellproliferation but allows cell migration. These cytostatic drugs, includefor the purpose of illustration and without limitation, macrolideantibiotics, rapamycin, everolimus, zotaroliumus, biolimus,temsirolimus, deforolimus, novolimus, myolimus, structural derivativesand functional analogues of rapamycin, structural derivatives andfunctional analogues of everolimus, structural derivatives andfunctional analogues of zotarolimus and any marcrolide immunosuppressivedrugs. The term “cytotoxic” as used herein means a drug used to inhibitcell growth, such as chemotherapeutic drugs. Some non-limiting examplesof cytotoxic drugs include vincristine, actinomycin, cisplatin, taxanes,paclitaxel, and protaxel.

Additionally or alternatively, the fluid can include other compounds oradditives, such as polymers, binding agents, plasticizers, solvents,surfactants, additives, chelators, fillers, and the like. Examples ofpossible compounds include zotarolimus, polyvinylpyrrolidone andglycerol. In one embodiment the therapeutic agent can be provided inliquid form or dissolved in a suitable solvent. In another embodiment,the therapeutic agent is provided as a particulate and mixed in asuitable carrier for application as a fluid.

An embodiment of the coating process and system of the disclosed subjectmatter is illustrated in FIG. 2 for purpose of explanation and notlimitation. The dispenser depicted herein is shown as a pipet 100 havingan outlet 102 positioned proximate expandable member 30 such that thefluid dispensed from the pipet is in continuous fluid contact with theexpandable member 30 without atomization of the coating solution. As thecoating solution is delivered from a fluid source, e.g. reservoir (notshown), through the dispenser outlet, a continuous fluid medium or bead200 of solution directly contacts the surface of the expandable member.

A positive pressure is applied to assist with dispensing fluid from theoutlet. Alternatively, the fluid can be dispensed from the outlet viacapillary action only, i.e., the surface tension pulls the bead ofcoating solution 200 onto the surface of the expandable member.Furthermore, the outlet can be heated prior to and/or during thedispensing of the coating solution. The heating of the dispenser canreduce the viscosity of the coating solution and therefore acceleratethe coating process as well as reduce the potential for clogging oroccluding of the dispenser outlet 102. FIG. 2 depicts the outletgenerally at a right angle to the balloon surface. However, alternativealignments and orientations can be used as desired or needed for thetype and dimensions of expandable members.

Coating process and systems of the disclosed subject matter can beperformed with the expandable member in a fully or partially inflatedcondition, as well as in a deflated condition. When deflated, theexpandable member can be pleated, folded, wrinkled or pressed. In theembodiment illustrated in FIG. 2, the expandable member is fullyinflated to allow coating of all or select portions of the outersurface.

As the fluid is delivered from the fluid source to the outlet 102 of thedispenser in the form of a continuous bead, relative movement isestablished between the outlet 102 and the expandable member 30 toeffect a uniform, or non-uniform, coating path as desired. For example,and as depicted in FIG. 2, the coating path can define a continuousspiral or helical pattern along the outer surface of the expandablemember. Alternatively, coating paths can be established such as discretecircumferential rings, discrete lines extending along the expandablemembers longitudinal axis, and combinations thereof. Hence, the relativemovement can include rotation, translation, or combinations thereof, ofeither, or both, the expandable member 30 and the outlet 102.

For example, the expandable member can be rotated about its centralaxis, as shown by arrows A in FIG. 2, and simultaneously translatedalong the central axis, as shown by arrow B in FIG. 2. Additionally, oralternatively the expandable member 30 can rotate relative a first axis,and the outlet 102 translate relative a second axis, e.g., to define ahelical coating path. Accordingly, any number of coating paths can beselected and provided on the expandable member. The various movementsdescribed herein can be performed simultaneously, sequentially,continuously or intermittently, as so desired.

Movement of the medical device and/or the outlet of the dispenser isaccomplished by providing a support assembly. The support assembly canmaintain the position of one element, e.g. the dispenser, while allowingmovement of the other element, e.g., the medical device. Alternatively,the support assembly can allow movement of both elements. Movement canbe performed manually, or by providing a drive assembly with suitabledrive source, such as a motor or the like, and appropriate controller asknow in the art.

Simultaneous with the relative movement, the fluid is dispensed from theoutlet to form a continuous bead between the outlet and the surface ofthe expandable member along the coating path. Generally, it has beendetermined that the formation and maintenance of the continuous bead offluid will be a function of the fluid density, and average velocity ofthe fluid from the outlet. In one embodiment, the Reynolds number, i.e.ratio of momentum or inertial force to viscosity, for the flow out ofthe outlet is less than 2300 such that the flow remains substantiallylaminar. The Reynolds number being defined by the equation Re=(ρ*v*l)/μwherein “l” is a dimension of the outlet. Additionally, the averagevolumetric flow rate of the fluid exiting the outlet lies within therange of 3-110 μl/min. It therefore is possible to form a substantiallycontinuous bead by controlling one or more of these variables. Forexample, the average velocity of the fluid can exit in the range ofapproximately 0.0411 to 4.11 cm/sec.

In one embodiment, the bead 200 diameter was maintained at apredetermined size of at least 0.03 in. Alternatively, bead diameters ofbetween 0.8 mm (or 0.03 in)and 2.5 mm (−0.1 in) for tubing innerdiameters between 0.006 inch to 0.20 inch are considered to be withinthe scope of the disclosed subject matter. In another embodiment, a 3.0mm×18 mm Pebax expandable member was rotated at 100 rpm, and translatedat a linear speed of 1.0 mm/sec which resulted in approximately 650μg/pass of a coating solution applied to the expandable member. Thecycle time for applying a coating to an expandable member can varydepending on the size of the expandable member, the flow rate of thecoating fluid, and the speed of relative movement, with a typical cycletime lasting from about 1 to 15 minutes. The rotational movement of theexpandable member provides an additional advantage of distributing thecoating solution around the circumference of the expandable member andpreventing any accumulation on the downward side due to gravity inducedflow. Additionally, or alternatively, as described further below, theapplied bead is dried to control and/or prevent a flow of the fluid onthe surface of the expandable member. To create the relative movementbetween the expandable member and dispenser, the expandable member waspositioned on a motorized mandrel geared to rotate and/or translate aswell as provide inflation/deflation of the expandable member.

In accordance with another aspect of the disclosed subject matter, thespeed at which the expandable member and/or outlet is moved can bevaried to modify a variety of coating properties including thickness,width and volume of the coating. For example, a slower speed of relativemovement between the elements will result in greater volume of fluid perpass. Similarly, the rate in which fluid is dispensed from the outletalso can be controlled to adjust or control the coating propertiesapplied to the surface of the expandable member. That is, a greater rateof fluid dispensed will result in a greater volume per pass if the speedof relative movement is maintained constant. Hence, any number ofcoating patterns and properties can be achieved by the disclosed methodand system.

The desired portions of the expandable member can be coated with asingle pass or cycle of relative movement between the expandable memberand dispenser. Alternatively, a plurality of passes or cycles of coatingoperation discussed above can be performed. Such multiple passes orcycles allows for further variation in the coating properties along theexpandable member length. For example, one portion of the expandablemember can be coated with a different number of coating layers of fluidthan another portion of the expandable member thereby creating agradient of the coating solution on the expandable member. Further, themethods and apparatus of the disclosed subject matter can be employed toapply layers of different coating compositions to the expandable member.For example, therapeutic-free primers, concentrated therapeutic layers,and drug-excipient layers can be applied. As discussed above, variedcoating properties allow for greater flexibility and customization ofthe catheter to provide a greater range of applications and ability tomeet patient needs.

In accordance with another aspect of the disclosed subject matter, adrying apparatus can be employed to control or prevent the flow of fluidapplied on the surface of the expandable member and to accelerate thecoating process. As shown in FIG. 2, a dryer 300 can be positioneddownstream of the dispenser to apply heat, forced gas, cooled gas,vacuum, infra-red energy, microwave energy, or a combination thereof tothe surface of the expandable member. Additionally, or alternatively,the drying nozzle 300 can be collinear or coaxial with the dispenser 100by either circumscribing the outlet 102 or otherwise surround the outletas with an annular opening, as shown in FIGS. 3-4. For example, thedrying operation can employ air, or ambient nitrogen, in a drying nozzleof 0.081 in, at a pressure of 5 to 25 psi, and a flow rate of about100-700 ml/min. As embodied herein, the flow rate can be calculated toequation: flow rate=(26.86*Pressure)+4.5204. Further, applying a dryinggas simultaneously, e.g. air or ambient nitrogen at 10 psi, evaporatessolvents contained in the fluid and facilitates drying of the coatingsuch that the coating disposed on the expandable member does not flow.In some embodiments, a drying operation can be conducted betweensuccessive coating passes or cycles. Additionally, or alternatively, thedrying operation can be conducted concurrently with a coating pass orcycle, as depicted in FIG. 2. Similar to the dispenser 100 discussedabove, the drying apparatus 300 can be oriented at any angle between0°-90° with respect to the expandable member, and be configured forrelative movement.

While the dispenser of the embodiment illustrated in FIG. 2 depicts adispenser configured as a pipet, additional or alternative dispenserscan be employed. Some examples of such dispensers include flexibletubing, coaxial tubing, hypotubes, dies, ball-bearing dispense tubing,syringe, needles, and other non-contacting applicators that are capableof forming a continuous bead. Furthermore, FIG. 2 depicts a dispenserhaving a single outlet 102 perpendicular to the expandable member thoughalternative angles between 0°-90° can be employed. Also, the use of aplurality of outlets can be employed. Each outlet can be orientedperpendicular, disposed adjacent each other along the axis of theexpandable member, and/or spaced circumferentially about the expandablemember.

In this regard, a plurality of reservoirs containing distinct coatingsolutions can be provided with each dispenser in fluid communicationwith a separate reservoir. As with the outlet of FIG. 2, the dispenserscan be positioned at various locations and orientations relative to theexpandable member. Additionally, the expandable member 30 can beoriented in a generally horizontal position, as shown in FIG. 2,vertically, or at or at any angle between 0°-90°, if desired. Orientingthe expandable member in a vertical configuration can be advantageous inlarger size expandable members, e.g. peripheral balloons, since thegravitational force acts parallel the expandable member's longitudinalaxis thereby preventing deformation such as arching or bowing of theexpandable member and associated catheter shaft, which the expandablemember can be susceptible to when in the horizontal position.

In accordance with another aspect of the disclosed subject matter, theoutlet of the dispenser is maintained at a predetermined or fixeddistance from the expandable member surface. Maintaining a fixeddistance between the dispenser outlet and the expandable member, incombination with uniform rotation and translation as discussed above,provides greater control over the coating pattern to be applied to theexpandable member surface. Such control can be advantageous by providinga consistent dosage of the therapeutic agent along the portion of theexpandable member.

Additionally, maintaining a fixed distance between the dispenser outletand the expandable member surface assists in maintaining a continuousbead of fluid from the outlet. For example, discrete droplets of fluidcould form if the distance between the outlet and the surface of theexpandable member were too great. Conversely, if the distance betweenthe dispenser outlet and the expandable member surface were too small,undesired or accidental contact between the outlet and expandable membersurface can occur resulting in tearing or scratching of the expandablemember surface or abrasion to the coating applied to the expandablemember. The distance between the outlet and the surface of theexpandable member can depend upon a number of variables, includingviscosity of the fluid, surface tension of the fluid, pump rate of thefluid, diameter of the dispenser exit orifice, volatility of thesolvents in the fluid, speed at which the fluid is dispensed and/or sizeof the outlet opening. For example, when using a pipet type dispenser,the distance between the outlet and the surface generally should be lessthan 40 times the smallest cross dimension of the outlet.

The fixed distance between the outlet and the surface of the expandablemember can be monitored in a number of ways in accordance with thedisclosed subject matter. Particularly, the fixed distance can bemonitored by displacing the outlet to track the surface, or bycontrolling displacement of the surface of the expandable memberrelative to the outlet. Examples of suitable methods and systems aredisclosed in U.S. patent application Ser. No. 61/345,569, which ishereby incorporated by reference in its entirety.

As discussed above, the coating method and system of the disclosedsubject matter can be performed on a previously assembled medicaldevice, e.g. balloon catheters. Often the force required to rotate orotherwise move the expandable member is applied to a location, and/orcomponent, proximal of the expandable member. Therefore, significantforce may be required to overcome the friction and inertia of thevarious components of the medical device in order to achieve movement ofthe expandable member. Thus, any reduction or minimization of points ofcontact between the encasement and expandable member is advantageous asthe frictional forces generated during the relative movement will inturn be minimized, thereby reducing the amount of force required by thesupport assembly, or manual operator, to establish relative movement. Asthe proximal components of medical device are often polymeric and nottorsionally rigid, undue friction on the expandable member can lead totorsional loading and unloading of the proximal members. This leads toinconsistent rotation of the medical device, which in turns leads tonon-uniform coating.

During the coating process, the catheter shaft 12 can be positionedwithin a support assembly to counteract the circumferential androtational forces and maintain the catheter shaft in a generally linearconfiguration. An example of such a support assembly is shown in FIG. 5,which includes a generally V-shaped structure 900 to define a channelfor receiving the catheter shaft 12. A retaining rod 1000 is positionedabove the shaft 12 and serves to obstruct or prevent the shaft 12 frombeing displaced out of the support assembly 900. In one embodiment, theretaining rod 1000 is configured with a cross-sectional dimension thatlimits the depth the retaining rod 1000 can be positioned within theV-shaped support assembly 900. Accordingly, the retaining rod 1000 isspaced from the shaft 12 to minimize contact, thereby minimizing thefrictional forces generated during rotation of the shaft. Similarly, thesupport structure 900 can be coated with, or fabricated from, alubricious material including Teflon, PEEK.

If desired, a protective sheath can be provided to protect the coatingduring shipping and storage and/or during delivery of the coatedexpandable member through the body lumen. A variety of sheaths areknown, including removable sheaths or balloon covers, retractablesheaths to be withdrawn prior to deployment of the balloon, and elasticsheaths that conform to the balloon upon expansion. Such elastic sheathscan be porous or include apertures along a portion thereof. Inoperation, the inflation of the expandable member causes the sheath toexpand for release of the coating and/or therapeutic agent through theporous wall or apertures to the tissue of the arterial wall. Forexample, see U.S. Pat. No. 5,370,614 to Amundson, the disclosure ofwhich is incorporated by reference in its entirety.

In accordance with in the disclosed subject matter, an endoprosthesis,e.g. stent, can be mounted on the expandable member. The type of stentthat can be used includes, but is not limited to, bare metal stent, drugeluting stent, bioabsorbable stent, balloon-expandable stent,self-expanding stent, prohealing stent, and self-expanding vulnerableplaque implant. The expandable member can be coated independently of thestent or in conjunction with the stent coating process. The stentcoating can contain the same or different therapeutic agents from thecatheter or expandable member. However, the particular coating on thecatheter or expandable member can have distinct release kinetics fromthe therapeutic coating on the stent. The coating applied to theexpandable member can be allowed to dry prior to placement of the stentthereon.

Alternatively, the coating could not be allowed to dry or cure past a“tacky” state before the stent is positioned and/or crimped onto it.This would enable the adhesion of the coating on the expandable memberto the inside of the prosthesis. This process increases the retention ofthe prosthesis onto the expandable member (acting as a prosthesisretention enhancer) thus reducing the chance that the stent will move onthe expandable member during the torturous delivery through the vascularlumen.

While the disclosed subject matter is described herein in terms ofcertain embodiments, those skilled in the art will recognize thatvarious modifications and improvements can be made to the disclosedsubject matter without departing from the scope thereof. Moreover,although individual features of one embodiment of the disclosed subjectmatter can be discussed herein or shown in the drawings of the oneembodiment and not in other embodiments, it should be apparent thatindividual features of one embodiment can be combined with one or morefeatures of another embodiment or features from a plurality ofembodiments.

In addition to the specific embodiments claimed below, the disclosedsubject matter is also directed to other embodiments having any otherpossible combination of the dependent features claimed below and thosedisclosed above. As such, the particular features presented in thedependent claims and disclosed above can be combined with each other inother manners within the scope of the disclosed subject matter such thatthe disclosed subject matter should be recognized as also specificallydirected to other embodiments having any other possible combinations.Thus, the foregoing description of specific embodiments of the disclosedsubject matter has been presented for purposes of illustration anddescription. It is not intended to be exhaustive or to limit thedisclosed subject matter to those embodiments disclosed.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the method and system of thedisclosed subject matter without departing from the spirit or scope ofthe disclosed subject matter. Thus, it is intended that the disclosedsubject matter include modifications and variations that are within thescope of the appended claims and their equivalents.

What is claimed is:
 1. A method of coating an expandable member of amedical device, comprising: providing a dispenser in fluid communicationwith a fluid source, the dispenser having at least one outlet todispense fluid of the fluid source therefrom; positioning the at leastone outlet of the dispenser proximate a surface of an expandable member;establishing relative movement between the at least one outlet and thesurface of the expandable member along a coating path; dispensing fluidfrom the dispenser to form a substantially continuous bead of fluidbetween the at least one outlet and the surface of the expandable memberalong the coating path; and simultaneously drying the fluid whiledispensing the fluid from the dispenser to control flow of fluid on thesurface of the expandable member.
 2. The method of claim 1, wherein thefluid remains substantially in a location where it contacts the surfaceof the expandable member.
 3. The method of claim 1, wherein relativemovement provides a velocity ranges approximately from 2 to 20 cm/sec.4. The method of claim 1, wherein the dispenser is selected from thegroup consisting of pipet, tubing, flexible tubing, hypotubes, dies, andball-bearing dispense tubing.
 5. The method of claim 1, wherein thedispenser does not contact the expandable member.
 6. The method of claim1, wherein the fluid includes a therapeutic agent.
 7. The method ofclaim 1, wherein the inflatable member is inflated to a pressure ofapproximately 0.1 to 8 atm prior to coating.
 8. The method of claim 1,wherein the dose density of therapeutic agent on the expandable memberis greater than 200 μg/cm².
 9. The method of claim 1, wherein therelative movement includes rotation, translation, or a combinationthereof, of at least one of the expandable member and the at least oneoutlet.
 10. The method of claim 9, wherein the relative movementincludes rotation, axial translation, or a combination thereof, of theother of the expandable member and the at least one outlet.
 11. Themethod of claim 9, wherein the medical device further includes a shaftextending from the expandable member, wherein during rotation andtranslation of the expandable member, the shaft remains straight. 12.The method of claim 9, wherein the medical device further includes ashaft extending from the expandable member, wherein during rotation andtranslation of the expandable member, a rotation torque is applied to aproximal hub disposed on the shaft.
 13. The method of claim 9, whereinthe relative movement includes moving the expandable member relative afirst axis, and moving the at least one outlet relative a second axis.14. The method of claim 9, wherein the relative movement defines ahelical coating path of the at least one outlet relative to theexpandable member.
 15. The method of claim 1, wherein dispensing fluidto the surface of the expandable member is repeated along a plurality ofcoating paths.
 16. The method of claim 15, wherein a first fluid isdispensed during a first coating path, and a second fluid is dispensedduring a second coating path.
 17. The method of claim 1, furthercomprising controlling dispensing to apply a substantially uniformcoating of fluid to a predetermined area of the expandable member. 18.The method of claim 1, wherein the at least one outlet is heated whiledispensing fluid therefrom.
 19. The method of claim 1, wherein thedispenser includes a plurality of outlets offset from each other.
 20. Asystem for coating an expandable member of a medical device, the systemcomprising: a support structure to support an expandable member of amedical device; a dispenser in fluid communication with a fluid source,the dispenser having at least one outlet for dispensing fluid of thefluid source therefrom, the dispenser positioned with the at least oneoutlet proximate a surface of an expandable member supported by thesupport structure; a dryer proximate the dispenser to simultaneously drythe fluid while dispensing the fluid from the dispenser to control flowof fluid on the surface of the expandable member; and a drive assemblyto establish relative movement between the at least one outlet and thesurface of the expandable member to dispense fluid from the dispenser asa substantially continuous bead between the at least one outlet and thesurface of the expandable member along a coating path.